Medicament microdevice delivery system, cartridge and method of use

ABSTRACT

A method and device for intradermal delivery of a reconstituted powdered medicament. The device includes a chamber, which is in fluid communication with a microdevice, e.g. microabrader or one or more microneedles. A cartridge containing the powdered medicament may be located within said chamber. At least one burstable membrane retains a powdered medicament within the housing. The method involves the steps of positioning the device at a delivery site on the skin of a patient and intradermally administering the medicament by dispensing a diluent from a diluent source an through inlet port to rupture the membranes, reconstitute the powdered medicament and deliver the reconstituted medicament through the microdevice to the dermal region of the skin.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to U.S. Provisional application60/474,592 filed Jun. 2, 2003 and is a continuation-in-part of U.S.patent application Ser. No. 10/141,849 Filed May 10, 2002, which is acontinuation in part of Ser. No. 09/879,517 filed Jun. 12, 2001 now U.S.Pat. No. 6,443,152 issued Sep. 3, 2002, which is a continuation in partof Ser. No. 09/758,776 filed Jan. 12, 2001 now U.S. Pat. No. 6,722,364,issued Apr. 1, 2004 all of which are herein incorporated by reference,in their entirety.

FIELD OF THE INVENTION

This invention relates to intradermal medicament delivery devicesincluding microabraders or microneedles, and their use to deliver apowdered medicament to a subject.

BACKGROUND OF THE INVENTION

The importance of efficiently and safely administering pharmaceuticalsubstances such as diagnostic agents and drugs has long been recognized.Although an important consideration for all pharmaceutical substances,obtaining adequate bioavailability of large molecules such as proteinsthat have arisen out of the biotechnology industry has recentlyhighlighted this need to obtain efficient and reproducible absorption(Cleland et al., Curr. Opin. Biotechnol. 12: 212-219, 2001). The use ofconventional needles has long provided one approach for deliveringpharmaceutical substances to humans and animals by administrationthrough the skin. Considerable effort has been made to achievereproducible and efficacious delivery through the skin while improvingthe ease of injection and reducing patient apprehension and/or painassociated with conventional needles. Furthermore, certain deliverysystems eliminate needles entirely, and rely upon chemical mediators orexternal driving forces such as iontophoretic currents orelectroporation or thermalporation or sonophoresis to breach the stratumcorneum, the outermost layer of the skin, and deliver substances throughthe surface of the skin. However, such delivery systems do notreproducibly breach the skin barriers or deliver the pharmaceuticalsubstance to a given depth below the surface of the skin andconsequently, clinical results can be variable. Thus, mechanical breachof the stratum corneum, such as with needles, is believed to provide themost reproducible method of administration of substances through thesurface of the skin, and to provide control and reliability in placementof administered substances.

Approaches for delivering substances beneath the surface of the skinhave almost exclusively involved transdermal administration, i.e.delivery of substances through the skin to a site beneath the skin.Transdermal delivery includes subcutaneous, intramuscular or intravenousroutes of administration of which, intramuscular (IM) and subcutaneous(SC) injections have been the most commonly used.

Anatomically, the outer surface of the body is made up of two majortissue layers, an outer epidermis and an underlying dermis, whichtogether constitute the skin (for review, see Physiology, Biochemistry,and Molecular Biology of the Skin, Second Edition, L. A. Goldsmith, Ed.,Oxford University Press, New York, 1991). The epidermis is subdividedinto five layers or strata of a total thickness of between 75 and 150μm. Beneath the epidermis lies the dermis, which contains two layers, anoutermost portion referred to at the papillary dermis and a deeper layerreferred to as the reticular dermis. The papillary dermis contains vastmicrocirculatory blood and lymphatic plexuses. In contrast, thereticular dermis is relatively acellular and avascular and made up ofdense collagenous and elastic connective tissue. Beneath the epidermisand dermis is the subcutaneous tissue, also referred to as thehypodermis, which is composed of connective tissue and fatty tissue.Muscle tissue lies beneath the subcutaneous tissue.

As noted above, both the subcutaneous tissue and muscle tissue have beencommonly used as sites for administration of pharmaceutical substances.The dermis, however, has rarely been targeted as a site foradministration of substances, and this may be due, at least in part, tothe difficulty of precise needle placement into the intradermal space.Furthermore, even though the dermis, in particular, the papillary dermishas been known to have a high degree of vascularity, it has notheretofore been appreciated that one could take advantage of this highdegree of vascularity to obtain an improved absorption profile foradministered substances compared to subcutaneous administration. This isbecause small drug molecules are typically rapidly absorbed afteradministration into the subcutaneous tissue, which has been far moreeasily and predictably targeted than the dermis has been. On the otherhand, large molecules such as proteins are typically not well absorbedthrough the capillary epithelium regardless of the degree of vascularityso that one would not have expected to achieve a significant absorptionadvantage over subcutaneous administration by the more difficult toachieve intradermal administration even for large molecules.

One approach to administration beneath the surface to the skin and intothe region of the intradermal space has been routinely used in theMantoux tuberculin test. In this procedure, a purified proteinderivative is injected at a shallow angle to the skin surface using a 27or 30 gauge needle (Flynn et al, Chest 106: 1463-5, 1994). A degree ofuncertainty in placement of the injection can, however, result in somefalse negative test results. Moreover, the test has involved a localizedinjection to elicit a response at the site of injection and the Mantouxapproach has not led to the use of intradermal injection for systemicadministration of substances.

As taught by published US application US 2003/0050602, when amicroneedle system is used for in vivo delivery, such as delivery to anintradermal space, a significant backpressure is encountered due toinstillation rate of fluid volume into and essentially sealed or closedspace having limited distensibility. This is true even thoughintradermal delivery of substances, such as medications, involve muchsmaller volumes if liquid, 100:L (microliters) for example, as comparedwith the volumes used in subcutaneous systems, which can be as large orlarger than 500:L (microliters). The magnitude of backpressure is alsoproportional to both the instillation rate as well as the volume. Thislevel of pressure is not typically encountered when delivering asubstance to the subcutaneous or intramuscular space, which is generallyregarded as a region of highly distensable tissue with a much higherlimit for instilled volume.

Some groups have reported on systemic administration by what has beencharacterized as “intradermal” injection. In one such report, acomparison study of subcutaneous and what was described as “intradermal”injection was performed (Autret et al, Therapie 46.5-8, 1991). Thepharmaceutical substance tested was calcitonin, a protein of a molecularweight of about 3600. Although it was stated that the drug was injectedintradermally, the injections used a 4 mm needle pushed up to the baseat an angle of 60. This would have resulted in placement of theinjectate at a depth of about 3.5 mm and into the lower portion of thereticular dermis or into the subcutaneous tissue rather than into thevascularized papillary dermis. If, in fact, this group injected into thelower portion of the reticular dermis rather than into the subcutaneoustissue, it would be expected that the substance would either be slowlyabsorbed in the relatively less vascular reticular dermis or diffuseinto the subcutaneous region to result in what would be functionally thesame as subcutaneous administration and absorption. Such actual orfunctional subcutaneous administration would explain the reported lackof difference between subcutaneous and what was characterized asintradermal administration, in the times at which maximum plasmaconcentration was reached, the concentrations at each assay time and theareas under the curves.

Similarly, Bressolle et al. administered sodium ceftazidime in what wascharacterized as “intradermal” injection using a 4 mm needle (Bressolleet al., J. Pharm. Sci. 82:1175-1178, 1993). This would have resulted ininjection to a depth of 4 mm below the skin surface to produce actual orfunctional subcutaneous injection, although good subcutaneous absorptionwould have been anticipated in this instance because sodium ceftazidimeis hydrophilic and of relatively low molecular weight.

Another group reported on what was described as an intradermal drugdelivery device (U.S. Pat. No. 5,997,501). Injection was indicated to beat a slow rate and the injection site was intended to be in some regionbelow the epidermis, i.e., the interface between the epidermis and thedermis or the interior of the dermis or subcutaneous tissue. Thisreference, however, provided no teachings that would suggest a selectiveadministration into the dermis nor did the reference suggest anypossible pharmacokinetic advantage that might result from such selectiveadministration.

Other methods of increasing skin permeability use various chemicalpermeation enhancers or electrical energy such as electroporation.Ultrasonic energy such as sonophoresis and laser treatments has beenused. These methods require complex and energy intensive electronicdevices that are relatively expensive. The chemical enhancers are oftennot suitable for intradermal drug delivery or sampling.

One example of a method for increasing the delivery of drugs through theskin is iontophoresis. Iontophoresis generally applies an externalelectrical field across the skin. Ionic molecules in this field aremoved across the skin due to the force of the electric field. The amountand rate of drug delivery using iontophoresis can be difficult tocontrol. Iontophoresis can also cause skin damage on prolonged exposure.

Sonic, and particularly ultrasonic energy, has also been used toincrease the diffusion of drugs through the skin. The sonic energy istypically generated by passing an electrical current through apiezoelectric crystal or other suitable electromechanical device.Although numerous efforts to enhance drug delivery using sonic energyhave been proposed, the results generally show a low rate of drugdelivery.

Other forms of transdermal drug delivery are also known, and one suchform uses pulsed laser light to ablate the stratum corneum withoutsignificant ablation or damage to the underlying epidermis. A drug isthen applied to the ablated area and allowed to diffuse through theepidermis.

Another method of delivering drugs through the skin is by forming micropores or cuts through the stratum corneum. Piercing the stratum corneumand delivering the drug to the tissue below the stratum corneum caneffectively administer many drugs. The devices for piercing the stratumcorneum generally include a plurality of micron-size needles or bladeshaving a length to pierce the stratum corneum without passing completelythrough the epidermis. Examples of these devices are disclosed in U.S.Pat. Nos. 5,879,326 and 6,454,755 to Godshall et al.; U.S. Pat. No.5,250,023 to Lee et al.; WO 97/48440; and WO 00/74763.

The prior methods and apparatus for the transdermal administration ofdrugs have exhibited limited success. Accordingly, a continuing needexists in the industry for an improved device for the intradermaladministration of various drugs and other substances.

Presently, storage-stability can be imparted to medicaments by placingthem in a dry powder form. Techniques for doing this includefreeze-drying, spray freeze-drying, lyophilization and the like. Somedry powdered medicaments have been directly administered by inhalation.See WO 95/24183 which relates to a dry powder form of insulin forinhalation.

To date, however, there remains a need for a system for the intradermaladministration of medicaments where the medicament is in a storagestable dry form, which can be readily reconstituted and directlyadministered via microdelivery devices such as, microabraders ormicroneedles and wherein the system utilizes the inherent backpressureof such intradermal or epdermal delivery to assist in the fluidicreconstitution of the dry medicament

SUMMARY OF THE INVENTION

The present invention involves devices and methods that integrate theessentially simultaneous fluidic reconstitution of a powdered medicamentwith the intradermal delivery or epidermal delivery of that fluid via amicro-delivery device (microdevice). Microdevices for disrupting thestratum corneum include microabraders and micron-sized needles(microneedles) or blades having a length to penetrate and substantiallypierce the stratum corneum without substantially penetrating into theunderlying dermis. Microneedles include structures with a diameterequivalent to or smaller than about 30 gauge, typically about 30-40gauge when such structures are cylindrical in nature. Non-cylindricalstructures encompassed by the term microneedles would therefore be ofcomparable diameter and include pyramidal, rectangular, octagonal,wedge, and other suitable geometrical shapes.

The devices of this invention exploit the benefits of having a drypowdered medicament formulation in conjunction with the increasedbioavailability and efficient delivery of microdevices. Medicaments caninclude pharmaceuticals, such as biopharmaceuticals, vaccines andnutrients including nutraceuticals, as well as such substances asanti-venom and antidotes for those exposed to poisons or biologicalagents, for example. An example of such dry powders which may be used inthe instant invention are described in U.S. patent application Ser. Nos.10/299,012 and 10/299,010 which are herein incorporated by reference inits entirety.

In some embodiments the dry powdered medicament can be stored andretained within a cavity in a housing. In one aspect of the invention amedicament is stored in a pre-filled carrier (“cartridge”) and isretained within the cartridge by two rupturable or pierceable films ormembranes sealed to either end of the cartridge. The cartridge, whenpresent, is placed into a cavity contained within the housing. Thehousing may also comprise an adapter, which is in fluid communicationwith the housing cavity and may be in the form of, for example, a tubeor conduit. The adapter may also contain a connector such as a Luerfitting that marries to a standard syringe or some other source ofliquid fluid such as a blow-fill seal container, liquid filled bulb orbladder, for example. The medicament delivery end of the devicecomprises a microdevice, e.g. a microabrader, or one or moremicroneedles, which is in fluid communication with the cavity of thehousing containing the medicament. A source of a solvent (“diluent”) maybe attached to the housing via the adapter in a removable fashion or maybe permanently attached, or integral with the housing. Regardless, thefluid diluent is not in contact with the dry powder prior to actuationof the device. To actuate the device, the user depresses on the plungerof the syringe or squeezes the bulb or otherwise activates the flow ofdiluent, discharging the fluid and rupturing the membranes retaining thepowdered medicament through the use of pressure or mechanical piercingelements, exposing the dry powder to the diluent. With the presence ofbackpressure normally encountered with intradermal delivery, theresidence contact time of the diluent and the powered medicament isimproved and assists with the reconstitution process. The same is truefor epidermal delivery, since the skin contacting an epidermal typedevice may act as a flow restrictor. The increased pressure generated bythe user's depression of the syringe or other activating mechanismessentially simultaneously forces the diluent into the chambercontaining the powdered medicament, the reconstitution of that powderedmedicament and the ejection of the formed diluent/medicament solutionout of the housing and into the skin intradermally via the microdevice.In another aspect of the invention, the membrane is ruptured with theaid of a piercing element simultaneously with activation of the device.In another embodiment, the membrane is ruptured by a piercing elementjust prior to activation of the device.

In one aspect, the invention provides a method for the intradermaldelivery of a substance to a subject by positioning the device of thisinvention at a delivery site on the skin of a patient, intradermallyadministering the medicament by applying the microdevice of the instantintradermal delivery device to the intradermal region of the skin of thesubject, dispensing a diluent into the intradermal delivery devicethrough the inlet port with sufficient force to rupture the at least oneburstable membrane, reconstituting the powdered medicament with thedispense diluent and substantially simultaneously delivering thereconstituted medicament through the outlet port to the microdevice at adelivery rate slower than the delivery rate of the diluent to thedelivery device.

In another aspect, the invention provides a method for the intradermaldelivery of a substance to a subject by positioning the device of thisinvention at a delivery site on the skin of a patient, intradermallyadministering the medicament by applying the microdevice of the instantintradermal delivery device to the intradermal region of the skin of thesubject, dispensing a diluent into the intradermal delivery devicethrough the inlet port while simultaneously piercing a membrane,reconstituting the powdered medicament with the dispense diluent andsubstantially simultaneously delivering the reconstituted medicamentthrough the outlet port to the microdevice at a delivery rate slowerthan the delivery rate of the diluent to the delivery device. In anotheraspect of the invention, the membrane is pierced just prior toactivation of the device.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows in cross section, a device that incorporate a microneedle.

FIG. 2 shows a pre-filled carrier of one aspect the invention withheat-sealed rupture membranes.

FIG. 3 shows a micrograph of the particles of SFD powders of one aspectthe invention.

FIG. 4 depicts a schematic side view of a device showing one aspect theinvention utilizing microabraders as the delivery means.

FIG. 5A, B, C, and D show one aspect the invention which incorporatespiercing elements to mechanically rupture the membranes in variousstages of its operation.

FIG. 6 is an exploded view of the embodiment of a microneedle deliverydevice shown in FIG. 1.

FIG. 7 is a graph depicting the results of using the microneedleembodiment of FIG. 6 to administer reconstituted ‘pure SFD insulin, i.e.without addition of cryoprotectant excipients.

FIG. 8 is a graph depicting the results of using the microneedleembodiment of FIG. 6 to administer an insulin/trehalose formulation.

FIG. 9 is a bar graph depicting the emitted dose results in terms ofpercent-emitted dose versus diluent volumes utilizing the device of FIG.6.

FIG. 10 shows water and oxygen barrier properties for a range ofcommercially available barrier films.

FIG. 11 shows the results of the testing described in ample 3.

FIG. 12 shows a schematic of a pump device, which incorporates aspectsof the invention.

FIG. 13 shows a cross-sectional schematic view of a device, which showsa sliding piercing element of one aspect of the invention.

DETAILED DESCRIPTION OF THE INVENTION

In one aspect the invention, the intradermal medicament delivery devicescomprises a housing comprising a chamber, an inlet port communicatingwith the chamber and an outlet port communicating with the chamber and amicrodevice portion of the device. Optionally, the outlet port iscoaxially aligned with the inlet port. The microdevice comprises one ormore microneedle or microabrader surfaces. A dry powdered medicament islocated within the housing chamber and preferably contained within acartridge comprising at least one fluid receiving opening and at leastone fluid discharge opening. The cartridge also comprises at least onepassage or cavity within. When placed within the housing chamber, the atleast one receiving and the at least one discharge openings of thecartridge are aligned with the inlet and outlet ports of the housing.The medicament is placed in the cartridge cavity or housing chamber andpreferably at least one burstable, polymeric membrane covers the passageat each of the fluid receiving and discharge ends of the housing orcartridge. Such polymeric membranes may be burstable either by pressureor by the use of one or more piercing element(s). The terms ‘burstable’or ‘rupturable’ are used interchangeably herein and are meant toindicate disruption of the barrier properties of the barrier material bysome means interalia piercing or mechanical fracture. In one embodiment,the housing can be formed of two releasably interconnected partsproviding access to the chamber for replacement of a disposable,pre-filled medicament cartridge. The releasable connection can beattained in a variety of ways including threaded attachment, a snap fitarrangement, clamps, bayonets, or other means known to those in the art.Snap fit attachment is most preferred for ease of assembly. Theintradermal delivery device may also include an adapter communicatingwith the chamber for receipt or attachment of a fluid delivery device,such as a syringe barrel or compressible bulb or bladder. If a syringeis to be used the adapter preferably includes a Luer connector adaptedto receive a syringe barrel for supplying fluid diluent through theinlet tube to the medicament containing chamber or cartridge. Theadapter may be in the form of a tube or conduit in fluid communicationwith the inlet port and the housing chamber. The adapter may also be aconduit which connects a source of diluent and the housing chamber. Theoutlet port may also include, or be in fluid communication with, atleast one outlet tube or channel, which is in fluid communication withthe microdevice that will deliver the reconstituted fluid medicament tothe subject. Microneedle(s), either hollow or solid, or a microabradersurface are the microdevices of preference so that the solution formedfrom the reconstituted medicament powder, can be administeredintradermally or epidermally. The powder is reconstituted by a fluiddiluent after rupture of the membranes on the opposed ends of thehousing or cartridge, if present, creating a substantially instantaneousfluid stream through the cartridge, dissolving the powder particles intothe fluid to form a solution. Fluidic pressure within the dry powdercontaining chamber, generated by the sizing of the at least one outletport and the backpressure created by the insertion of the microdeviceinto the intradermal or epidermal site of the subject results in adevice and method that essentially simultaneously reconstitutes thepowdered material and delivers the reconstituted substance intradermallyor epidermally.

In one aspect of the invention, the cartridge for use in the intradermalmedicament delivery device and methods for its preparation and fillingwith medicament is described in U.S. application Ser. No. 09/879,517,filed Jun. 12, 2001, the contents of which are expressly incorporatedherein by reference. In this embodiment, the cartridge includes a bodyhaving opposed ends, a passage through the body and through the opposedends, a medicament is stored in the passage and burstable or rupturableor pierceable membranes cover and seal the passage at the opposed endsof the body. The burstable membranes can be ruptured either by pressureor by physically piercing the membrane with a piercing element, such asthat shown in U.S. Pat. No. 6,443,152, issued on Sep. 3, 2002, theentire contents which are expressly incorporated herein by reference Itmay be of benefit to have the opposed ends of the cartridge bodysurrounding the passage be convex and the membranes are therebystretched taut over the convex opposed ends and bonded thereto, sealingthe passage. The opposed ends of the body may be frustoconicalsurrounding the passage and the membranes may comprise a thin burstablepolyolefin film heat-sealed or fused to the opposed frustoconical endsof the body. An annular groove may be provided at the mid-portion of thecartridge body for ease of handling. Optionally, the interior passagemay also contain baffles to deflect or disrupt the fluid flow therethrough.

The polyolefins include polyethylene, polypropylene, ethylene-alphaolefin copolymers. The polymeric films which form burstable membranesare preferentially oriented polyolefin films (membrane), preferablyuniaxially oriented polyethylene films, angularly related, wherein thefilms oriented on the opposed ends of the cartridge are most preferablyoriented at approximately right angles. Burstable membranes formed ofpreferentially or uniaxially oriented polyolefin film should be orientedat approximately right angles to the passage, which results in improveddelivery of the medicament. Polyolefin films can be oriented by drawingin one or both mutually perpendicular directions in the plane of thefilm to impart strength thereto using methods known in the art.

Prototype testing indicates that the pressure-burstable membranes at theopposite ends of the cartridge in the delivery devices of this inventionrupture nearly simultaneously using only a modest pressure. Where themembranes are preferentially or uniaxially oriented and perpendicular,the membranes each rupture in a slit near the center along the axis ofthe oriented films at approximately right angles to one another.Although not requisite for operation of the invention, it is theorizedthat this type of rupture requires the fluid to turn as the fluid israpidly transmitted through the passage, mixing with and dissolving themedicament and entraining the fluid medicament through the slit formedin the second membrane. It has been found that when the fluid used toentrain the powdered medicament was in the form of a gas, the generallyperpendicular orientation of the preferentially or uniaxially orientedfilms oriented at right angles in this embodiment resulted in an emitteddose of about 97%. Similar result would be expected with the fluid inthe form of a liquid.

The employment of mechanical piercing elements enables the use of highbarrier films, which may be too strong for bursting via use of pressurealone. Such high barrier films allow longer storage shelf life for thepowder medicaments. Examples of high barrier films include, but are notlimited to, higher gauge polyolefin monolayer and multilayer films,including those containing cyclo-olefins, metalized films, as well asother commercial films. FIG. 10 shows the water and oxygen barrierproperties for a range of commercially available barrier films. Barrierproperties of the materials making up the primary drug container are themost significant factors affecting drug stability. Oxidation can lead todrug degradation and precipitation. In addition the transport of watervapor into or out of the package will affect the drug concentration.High water vapor barrier is particularly critical for drugs stored indry form since introduction of water may greatly accelerate certaindegradation pathways in these drugs. Use of other examples of such filmswill be obvious to those skilled in the art.

The method of delivering a medicament to a subject comprises providing amedicament delivery device comprising a housing that comprises a chambertherein, an inlet port communicating with the chamber, and an outletport communicating with said chamber; a cartridge, if utilized is placedwithin the housing chamber and the cartridge comprises a passage, afluid receiving opening and a fluid discharge opening, both openingscommunicating with the passage. A dry powdered medicament is alsocontained within the housing chamber and preferably within thecartridge. A microdelivery device sized to penetrate into the stratumcorneum, intradermal space, or to disrupt the stratum corneum is alsocomprised by the device.

At least one burstable membrane is sealingly attached to at least one ofthe housing openings or cartridge ports to retain the powderedmedicament within the chamber or cartridge. Lastly an adaptercommunicating with the housing inlet port and adapted to communicatewith a source of a fluid diluent is included in the device. The methodthen includes selecting a site for administration and then compressingthe manually compressible fluid delivery device to deliver fluid to theinlet of the cartridge, rupturing the burstable membrane, dissolving orthe medicament in the fluid and delivering the medicament to theselected site. Other attendant steps may be involved depending on themicrodevice selected. A microneedle requires penetration of the stratumcorneum prior to or concurrently with the actuation step. Themicroabrader requires the stratum corneum to be abraded prior to,jointly with, or after the actuation step.

Many of the current liquid based therapies require the addition ofexcipients or preservatives to ensure the integrity of the activitythrough storage. These excipients and preservatives may cause skinirritation. Dry powders are generally more stable and maintain activitywithout the use of a preservative and thereby possibly avoid skinirritation. The devices of the invention maintain the drug formulationas a dry stable form until immediately prior to delivery, prolonging itsoverall stability and storage lifetime.

It has been shown that Spray Freeze Dried (SFD) powders lend themselvesto more instantaneous reconstitution into solution due to the porousmorphology of the particles. This provides a benefit over other powdersamples that are prepared by milling, lyophilization or spray drying,where significant agitation or mixing must occur to get the dry powderinto solution prior to delivery. The ease of reconstitution of SFDpowders permits the integration of all of the steps into one injection.

Additional baffles and other mixing elements may be added to the fluidpath of the device, either in the housing or the cartridge, increasingthe contact time between the diluent and the dry powder, ensuring propermixing and reconstitution prior to delivery. In place of a syringe,diluent containing bladders or other diluent containing devices may beutilized to transfer the diluent into the dry powder container. Ports orrupture membranes may also be located between the diluent-containingdevice and the dry powder container to prevent re-filling or reuse ofthe device if so desired. This prevention of the refilling or reuse ofthe device could also be accomplished, for example, through the use ofone-way valves, pressure fittings, or other such means.

The SFD powders may also allow the formation of supersaturatedsolutions. The rapid reconstitution and administration to the patientenabled by the devices of this invention permits solutions to bedelivered to the patient without precipitation. This allows for reducedintradermal injection volumes for administration of a given dose.Reduced injection volume in turn may reduce the edema and erythemaformed at the injection site, and thus reduce physiological perceptionof discomfort.

An additional benefit is that the use of dry powder forms of medicamentsin a pre-filled, unit dose delivery device can eliminate the need foranti-microbial additives or other preservatives such as phenol ormeta-cresol, which are found in many solution formulations ofpharmaceuticals. Intradermal administration of phenolics and otherpreservatives is known to cause localized tissue damage, which isavoided by use of the in situ drug reconstitution method of delivery ofthis invention.

An additional benefit is the enhanced immune response that can beachieved with SFD vaccines administered with such a prefilled injectiondevice such as this invention. Such SFD vaccines are described inco-pending U.S. patent application Ser. No. 10/299,012, filed on Nov.19, 2002, the contents of which are expressly herein incorporated byreference.

The intradermal medicament delivery device, cartridge, and method ofdelivering a medicament to a recipient will now be described withreference to the accompanying drawings, in which preferred embodimentsof the inventions are shown. However, as will be understood by thoseskilled in this art, the drawings are intended to be merely illustrativeof preferred embodiments, and this invention should not be construed aslimited to the embodiments disclosed in the drawings, wherein likenumbers refer to like elements throughout.

One embodiment of the cartridge 20 for use with an intradermalmedicament delivery device is shown in FIGS. 1 and 2. The cartridge 20includes a body 22 having a passage 23 extending through the body 22through the opposed ends 26 and 28. Also shown in FIG. 1 are optionalbaffles 49. The passage 23 is sealed at the opposed ends 26 and 28 ofthe body 22 by polymeric films or membranes preferably polyolefin films30 and 32 respectively, having a burst pressure of less than 10atmospheres, most preferably less than 5 atmospheres. The cartridge 20fits within the chamber 29 defined by the two housing portions 42 and45. Optional annular groove 51 in cartridge 20 is provided at the midportion of the body 22 for ease of handling.

FIG. 6 shows the relation of cartridge 20 and an optional “O” ring 61,which helps properly position the cartridge 20 and provides a fluidtight seal when the cartridge 20 is secured in the chamber 29, formed bythe housing portions 42 and 45. It is possible to achieve a fluid tightseal without the use of an “O” ring, in which case it would be omittedfrom the assembly. As shown in FIG. 6 the housing portion 42 containingthe microneedle 50 contains a male threaded portion 43, which allows itto be releasably attached to the housing portion 45. Housing portion 45preferably contains a Luer fitting 46 and having a female threadedportion 44 adapted to receive the threaded portion 43 of housing portion42. The housing portions 42 and 45 fit together to form a fluid tightseal when all the components are secured within. This manner of joiningalso insures a tight fluid seal with referenceto the “O” ring 61. Theuse of the threaded connectors 443 and 44 insures a more even pressureacross the surface of the “O” ring. A second “O” ring 52 may also beemployed, and would be placed at the opposite end of the cartridge 20and the housing portion 45. (See FIG. 4).

FIG. 4 shows a second embodiment where housing portion 42 has beenadapted for use with a micro abrader surface 62. The housing portion 42has an optional recess 71 for receiving the “O” ring 61. The recess 71positions the “O” ring 61 in place to hold the cartridge 20 in a desiredposition relative to an outlet 65 in fluid communication with tube orchannel 64. Channel 64 is then in fluid communication with interiorchamber 29, which contains cartridge 20. In use the contents ofcartridge 20 will pass through outlet 65 to channel 64 and alongpassages 63 located on the sides of housing portion 42 so that themedicament is conveyed to the site of administration 62.

With regard to a releasable connection between the housing portionsshown in the above preferred embodiments, it is also envisioned thatmeans other than the pictured male and female threaded arrangement, suchas a friction or a spring action clip involving a recess and a springloaded protrusion or the like which cooperates with a recess to lock thehalves in place.

FIGS. 5A-D show a schematic of an embodiment of a microneedle device invarious stages of discharge. This embodiment incorporates piercingelements to mechanically rupture the membranes 30, 32. The depictedalternative version contains an integral housing 80 defining a chamber79 into which the cartridge 20 is placed. The housing 80 contains amicroneedle 50 integral with a protrusion 81, capable of mechanicallyrupturing the polymeric film 30, 32 placed at one end 26, 28 of thecartridge 20 and providing fluid communication with the cartridgepassage 23 upon rupture of the polymeric film. A fluid-containingreservoir 82 contains a shaped protrusion 83, within reservoir chamber85, which is capable of rupturing the polymeric film placed at one end26, 28 of the cartridge and providing fluid communication with thecartridge passage 23 upon rupture of the polymeric film. The fluidcontaining reservoir 82 contains a seal 84 at the end opposite to theprotrusion. The seal 84 is displaceable when pressure is applied to it,displacing the fluid contained within chamber 85 and through a passagein the protrusion 83 (not shown) and into the cartridge passage 23,dissolving the medicament contained therein to form a medicamentsolution. Alternatively, protrusion 83 is solid and a secondary passageis used to allow fluid communication. The medicament solution is thenforced through the hollow microneedle 50. The fluid-containing reservoir82 is movable within the chamber 79 of housing 80. Together, 80 and 82form a liquid seal with the sides of the chamber 29. The movement of thefluid reservoir 82 causes the polymeric films to be mechanicallyruptured by the integral microneedle protrusion 29 and the protrusion83. The rupture of the polymeric films can be simultaneous or not. It isalso possible to select films that do not require mechanical but rathercan be ruptured by fluid pressure alone and modify the deviceappropriately to contain a microneedle without one or both of theintegral protrusion 29 and the protrusion 83, depending on the placementof the polymeric film at the cartridge end 26, 28. The protrusion andthe integral microneedle protrusion are coaxially aligned in thisembodiment.

As will be understood from the above descriptions of the aspects of theinvention and the following examples, the method of delivering amedicament to a recipient and the medicament delivery device of thisinvention preferably delivers the medicament at a relatively modestpressure to the recipient as compared to other devices requiring alesser pressure, such as subcutaneous devices. In some embodiments ofthe medicament delivery device, fluid pressure is delivered to the inletof the cartridge by a manually compressible fluid delivery device, suchas a syringe or collapsible bulb, or bladder. In other embodiments ofthe invention, the fluid pressure is delivered via a pump. In the caseof pressure burstable membranes, it is desired to have the burstpressure of the burstable membranes 30 and 32 between 1.2 and 10atmospheres or more preferably less than 5 atmospheres and mostpreferably between 1.5 and 4 atmospheres, for ease of operation. Theselimited ranges do not apply for membranes that are mechanically burst.The passage 23 through the body of cartridge 20 serves as a vessel orreservoir containing a suitable medicament. As set forth above, anddescribed further below, the medicament may be any medicament, drug orvaccine or combinations thereof used in the prevention, alleviation,treatment or cure of diseases. Examples of such medicaments are setforth below. In the disclosed embodiment, the passage 24 includes a unitdose of a powder medicament.

As shown in FIG. 1, the body 22 of the cartridge is preferablycylindrical having an intermediate or central V or U-shaped groove 51for ease of handling and, where the cartridge is replaceable, the bodyportions on opposed sides of the central groove 51 may be symmetricalsuch that the cartridge 20 may be loaded into the intradermal medicamentdelivery device described below in either orientation, avoiding mistakesin assembly of the device. The passage 23 is preferably cylindrical, butmay also be hourglass shaped, rectangular or shaped in otherconfiguration depending upon the medicament, actuation means, or otherconsiderations.

From the disclosure of Published U.S. Application 2003/0050602 publishedMar. 13, 2003, herein incorporated by reference in its entirety, it isdemonstrated that intradermal delivery produces higher backpressure thandoes subcutaneous delivery, and in some aspects of the invention thedevice utilizes that backpressure (from about 2.5 to about 20 psi) toassist in the substantially simultaneous reconstitution of the driedmaterial h the device and the delivery of that reconstituted material toa subject. In the case of epidermal delivery, the backpressure isgenerated by the contact sealing of the device against the skin oralternatively by the sizing of such conduits that lead to the skin.

The device of FIG. 12 shows aspects of the invention incorporatingautomatic delivery of the reconstitution fluid via a pump. Housing 45and 42 contain a reservoir 196 and driver 200. Reservoir 196 containsthe reconstitution fluid which, when the device is activated, isexpelled by driver 200 first to cartridge 20, then to a microdevicewhich is engaged to the patent. Driver 200 may be a Beliville spring,suitable pump or other drive mechanism known in the art. Sample driversmay be adapted from mechanisms described in U.S. patent application Ser.No. 10/112,757, filed Apr. 2, 2002 and U.S. Pat. Nos. 6,702,779 and6,656,147 all of which describe such drive mechanisms in detail, and allof which are herein incorporated by reference in their entirety. Whenthe driver is activated, fluid flows from reservoir 196 via firstconduit 265, which flows past burstable membrane 30 on cartridge 20,through passage 23, past burstable membrane 32, through conduit 65 tomicroneedle(s) 50 and into the patient. The burstable membranes may beburst mechanically, as discussed previously, or by fluid pressuregenerated by driver 200.

Reservoir 196 in preferred embodiments is dimensioned to contain areconstitution fluid to reconstitute a unit dose of a substancecontained in cartridge 20 to be delivered to the patient. Preferably,membranes 30 and 32 and conduits 265 and 65 form a fluid-tight seal tocartridge 20, and membranes 30 and 32 are burst just prior to deliveryof the fluid to the patent. Outer wall 262 supports one or more skinpenetrating members 50, in this case microneedles. In some embodiments,microabraders are arranged in an array of rows and columns spaced apartby a substantially uniform distance. Typically, skin-penetrating members50 are microneedles projecting from outer wall 262 at such a length toaccess the intradermal compartment and are arranged in an array designedto deliver an effective amount of a substance through the skin of apatient over a selected period of time. Typically, the needle array hasan area of about 1 cm² to about 10 cm.², and preferably about 2-5 cm².

The device of FIG. 13 shows another aspect of the inventionincorporating a sliding piercing element. In this embodiment, housingportion 42 has been adapted for use with a micro abrader surface 62. Thehousing portion 42 has been affixed to housing portion 45. Engagement ofthe two separate of housing portions 45, 42 is via a fluid-tightconnection which may be accomplished via methods well known in the art,inter alia sonic welding. Alternatively, housing portions 45, 42 may beintegrally formed from a single part. In some cases it may be desirableto have housing portions 45 and 42 permanently attached and in othercases a releasable attachment may be used. Interior chamber 29 is formedwithin housing portions 42 and 45. Chamber 29 contains cartridge 20 in adesired position relative to an outlet 65 in fluid communication withtube or channel 64. Cartridge 20 is slidably engaged to the walls ofchamber 29 such that a substantial fluid-tight seal is maintained; yetcartridge 20 is free to move axially within chamber 29. Optionally,cartridge 20 is integrally formed into chamber 29 and is not movable.Optionally, at the distal end of chamber 29 is piercing element 350.Channel 64 is then in fluid communication with interior of chamber 29,which contains cartridge 20. In use, the contents of cartridge 20 willpass through outlet 65 to channel 64 and along passages 63, in thiscase, located at the central portion of housing portion 42 so that themedicament is conveyed to the site of administration 62. Alternatively,if a microneedle is used, the medicament is conveyed into the patientvia a microneedle.

Chamber 29 also houses slidable carriage 500, which has distal end 545and proximal end 535. On distal end 545 of carriage 500 is piercingelement 83. Carriage 500 also has cavity 565 and passage 583 which arein fluid communication. An exterior portion 520 of carriage 500 engagesthe walls of chamber 29 such that carriage 500 is slidable along anaxial direction. Additionally, the engagement of exterior portion 520 ofcarriage 500 to walls is substantially fluid-tight, such that fluid ispreferentially routed through cavity 565 and subsequently throughpassage 583.

Housing portion 45 may contain a Luer fitting 46 or other fitting sothat a fluid supply device, as described previously, may be attached tohousing 45. As the device of FIG. 13 is affixed onto a fluid supplydevice or fluid line, proximal end 535 of carriage 500 interferes withthe distal end of the fluid supply device or line, such that carriage500 is moved axially in the distal direction, until such point thatpiercing element 83 pierces membrane 32. Alternatively, the axialmovement of carriage 500 within chamber 29 is accomplished by the fluidpressure of the fluid supply impinging on the proximal half of carriage500, within chamber 29, and no interference of carriage and distal endof the fluid supply is required. The device is then actuated such thatfluid is expelled from the fluid supply through cavity 565 and passage583 into cartridge 20 which houses the medicament, as describedpreviously. Alternatively, in one particular embodiment, the fluidpressure builds within cartridge 20 such that cartridge 20 is moveddistally within chamber 29 such that piercing element 350 piercesmembrane 30. In another embodiment, cartridge 20 is moved distally bycontact with the distal end 545 of carriage 500, such that, aftermembrane 32 is pierced, carriage 500 continues to move distally untilpiercing element 350 breaches membrane 30. In another embodiment wherecartridge 20 is integrally formed or attached to the walls of chamber29, bursting of membrane 30 is accomplished by pressure only.

As will be understood, the medicament delivery device and cartridge ofthis invention may be utilized to deliver various substances includingmedicaments via a intradermal or epidermal route used in the prevention,diagnosis, alleviation, treatment or cure of diseases. In addition,certain aspects of the delivery device of the invention may be useful inother routes of administration, such as inter alia parenteral,subcutaneous, intramuscular or intravenous delivery. Medicaments whichmay be delivered by the medicament delivery devices and methods of theinvention by the may take other forms, other than the specific SFDpowder which is described above such as inter alia lyophilized powders,particles, solutions, and suspensions. Specifically, medicaments in theforms of particles, micro-particles, nano-particles, which are entrainedto form a suspension, may also be delivered by the devices and methodsof the invention. A non-inclusive list of applicable substances mayinclude, for example, (i) drugs such as Anti-Angiogenesis agents,Antisense, anti-ulcer, butorphanol, Calcitonin and analogs, COX-IIinhibitors, desmopressin and analogs, dihydroergotamine, Dopamineagonists and antagonists, Enkephalins and other opioid peptides, Growthhormone and analogs (including growth hormone releasing hormone), Growthhormone antagonists, IgE suppressors, Insulin, insulinotropin andanalogs, Ketamine, Kytril, Leutenizing hormone releasing hormone andanalogs, lidocaine, metoclopramide, Midazolam, Narcotic analgesics,neuraminidase inhibitors, nicotine, Non-steroid anti-inflammatoryagents, Oligosaccharides, ondansetron, Parathyroid hormone and analogs,Parathyroid hormone antagonists, Prostaglandin antagonists,Prostaglandins, Recombinant soluble receptors, scopolamine, Serotoninagonists and antagonists, Sildenafil, Terbutaline, vasopressin; (ii)vaccines with or without carriers/adjuvants such as prophylactics andtherapeutic antigens (including but not limited to subunit protein,peptide and polysaccharide, polysaccharide conjugates, toxoids, geneticbased vaccines, live attenuated, reassortant, inactivated, whole cells,viral and bacterial vectors) in connection with, arthritis, cholera,cocaine addiction, HIB, meningococcus, measles, mumps, rubella,varicella, yellow fever, Japanese encephalitis, dengue fever,Respiratory syncytial virus, pneumococcus, streptococcus, typhoid,influenza, hepatitis, including hepatitis A, B, C and E, polio, HIV,parainfluenza, rotavirus, CMV, chiamydia, non-typeable haemophilus,moraxella catarrhalis, human papilloma virus, tuberculosis includingBCG, gonorrhoea, asthma, atheroschlerosis, malaria, otitis media,E-coli, Alzheimer's, H. Pylori, salmonella, diabetes, cancer and herpessimplex; and (iii) other substances in all of the major therapeuticssuch as Agents for the common cold, Anti-addiction, anti-infectives,analgesics, anesthetics, anorexics, antiarthritics, anti-allergy agents,antiasthmatic agents, anticonvulsants, antidepressants, antidiabeticagents, anti-depressants, anti-diuretics, anti-emetics, antihistamines,anti-inflammatory agents, antimigraine preparations, antimotion sicknesspreparations, antinauseants, antineoplastics, antiobesity,antiosteoporeteic, antiparkinsonism drugs, antipruritics,antipsychotics, antipyretics, antitussiers, anticholinergics,benzodiazepine antagonists, bone stimulating agents, bronchial dilators,central nervous system stimulants, corticosteroids, hormones, hypnotics,immunosuppressives, mucolytics, prostaglandins, proteins, peptides,polypeptides and other macromolecules, psychostimulants, rhinitistreatment, sedatives, sexual hypofunction, tranquilizers and vitaminsincluding B12.

EXAMPLE 1

Spray-Freeze Dried (SFD) Insulin was prepared in the manner according toU.S. Patent Application Ser. Nos. 60/419,959 and 10/299,012, filed Oct.22, 2002 and Nov. 19, 2002, respectively, the contents of which areherein expressly incorporated by reference. Single dosage amounts of apowder formulation of insulin were placed in the cartridge of devices inaccord with that shown in FIG. 1, and sealed. The cartridge was thenplaced in the chamber of the device so that the ends aligned with theinlet and outlet. A 1.0 mm 34-gauge needle with an additional side portoutlet was employed as the microdevice. A glass micro syringe was filledwith diluent and positioned within the Luer fitting. The micro deliverydevice assembly was placed against the flank of a diabetic swine and thesyringe plunger depressed, reconstituting the insulin powder, which wasthen injected into the animal. Blood samples were taken at 5, 10, 15,20, 30, 40, 50, 60, 75, 90, 120, 150, 180, 240, 300, and 480 minutes.Blood glucose and insulin levels were recorded at each time point. Theresults are shown in FIGS. 7 for SFD Insulin (8.1 IU) and for SQ HumulinInsulin (10 IU) and in FIG. 8 for SFD Insulin/trehalose (10.2 IU) and SQHumulin (10 IU).

The results were analyzed. C_(max) was found to be much higher forReconstitution-ID delivery of SFD Insulin formulations than SQ Humulininjections. Reconstitution ID delivery allowed a more rapid onset ofabsorption versus SQ as measured by t_(max) (t_(max) Reconstitution=51minutes vs. t_(max) SQ=120 minutes).

The insulin formulations used during this trial were stored in adessicator at room temperature for 4 months (Ins/Tre) and 10 months (Insonly). Both formulations retained their activity and readily went intosolution at time of injection.

EXAMPLE 2

In order to quantify the level of emitted dose, medicament was injectedinto euthanized swine using devices in accordance to FIG. 1. The devicescontained SFD Insulin/Trehalose at doses of 10.9 to 13.09 UI and wereattached to diluent reservoirs containing either 25 μl, 50 μl, 100 μl,or 150 μl of diluent. The diluent used was 0.9% sodium chlorideInjection USP. The devices were rinsed with 500 μl EDTA-solution aftereach injection. The rinses were analyzed using HPLC to determinenonemitted dose. The emitted dose was calculated by difference. Resultsare shown in FIG. 9. The emitted dose at 25 μl is 79.6%. The emitteddose at 100 μl is 92.6%. There is a loss of only 13% emitted dose with a75% reduction in diluent volume. This reduction in emitted doseinjection volume is beneficial to reduce the discomfort associated withinjection.

The insulin formulations used were stored in a dessicator cabinet atroom temperature for 4 months (Ins/Tre) and 10 months (Ins only).

EXAMPLE 3

Luciferase plasmid (pCMV-Luc from Aldevron, 2 μg/mL in H₂O) was sprayfreeze-dried and loaded into cartridges by the process previouslydescribed. Each cartridge was loaded to contain 10 μg of plasmid. Theloaded cartridge was inserted into a housing, which was in directcommunication with a snap-fit adapted 1cc tuberculin syringe. Thehousing itself was integrated with a microabrader device in accord withthat shown in FIG. 4, with a fluid path terminating in a port openingjust above the abrading surface, so that reconstituted medicament flowedonto the skin in front of the abrading surface during administration.The syringe was loaded with 250 μl of normal saline. After compensationfor device dead-space, the amount of reconstituted SFD-plasmid deliveredwas approximately 50 μl. The syringe was slowly depressed, immediatelyreconstituting the SFD-plasmid and releasing a 50 μl drop of plasmidsolution onto the shaved back of a Brown Norway Rat. The microabraderdevice was then passed over the plasmid solution 4 times in alternatingup and down passes. This process was repeated on 4 other sites for 5replicates of the condition. Treated sites were excised 24 hourspost-treatment and analyzed for luminescence against untreated skin. Thegraph in FIG. 11 shows the results of this analysis. In FIG. 11RLU=Relative luminescence units, B/G=Background (negative control), andthe Reconstitution/Delivery Device was the microabrader device of FIG.4.

Sites treated with the reconstituted Luciferase plasmid producedluminescence significantly above the negative control. Therefore, onemay conclude that the cells in the rat skin were transfected withLuciferase plasmid and Luciferase protein was produced. Severalconclusions can be drawn from this data. The SFD process did not disablethe plasmid's ability to transfect cells. The passage of a fluid throughthe cartridge was sufficient to reconstitute the SFD-plasmid. Themicroabrader device successfully accessed living cells in the skin.

Thus, it is seen that an intra-dermal delivery device, having amembrane, a microdevice and a medicament and method of deliveringmedicament to the subject using the intradermal delivery device has beendescribed and disclosed. It will be apparent that the present inventionhas been described herein with reference to certain preferred orexemplary embodiments. The preferred or exemplary embodiments describedherein may be modified, changed, added to, or deviated from withoutdeparting from the intent, spirit and scope of the present invention.

1. A dermal delivery device comprising: a housing comprising a chamber,an inlet port communicating with said chamber, and an outlet portcommunicating with said chamber; a cartridge, wherein said cartridgecomprises a passage, a fluid receiving opening and a fluid dischargeopening, both openings communicating with said passage; a dry powderedmedicament; a microdelivery device sized to penetrate into the stratumcorneum, intradermal space, or to disrupt the stratum corneum, withoutsubstantially penetrating into the underlying dermis; at least oneburstable membrane sealingly attached to one of said ports to retainsaid powdered medicament within said chamber; and an adaptercommunicating with said inlet port and adapted to communicate with asource of a fluid diluent.
 2. The dermal delivery device of claim 1wherein said powdered medicament is contained in said cartridge and saidat least one burstable membrane is sealingly attached to at least one ofsaid at least open cartridge opening.
 3. The dermal delivery device ofclaim 1, wherein said microdelivery device comprises one or more stratumcorneum disrupting protrusions selected from the group consisting ofmicroabraders, microblades, and microneedles.
 4. The dermal deliverydevice of claim 1, wherein said microdelivery device comprises one ormore microneedles, selected from the group consisting of solidmicroneedles, hollow microneedles and combinations thereof.
 5. Thedermal delivery device of claim 1, further comprising a conduit in fluidcommunication with said outlet port and said microdelivery device. 6.The dermal delivery device of claim 1, further comprising a fluiddiluent container permanently attached to said adapter.
 7. The dermaldelivery device of claim 1, wherein said adapter is a Luer connector forfluidly connecting said adapter to a syringe.
 8. The dermal deliverydevice of claim 1, wherein said at least one burstable membrane isburstable by the application of pressure thereto.
 9. The dermal deliverydevice of claim 1, further comprising a mechanical puncturing elementfor puncturing at least one of said at least one burstable membrane. 10.The dermal delivery device of claim 1 wherein said adapter comprises aninlet tube communicating with said inlet port and said chamber having aLuer connector adapted to receive a syringe barrel.
 11. The dermaldelivery device as defined in claim 1, wherein said housing is formed oftwo releasably interconnected components and one of said componentsincludes a generally cylindrical cartridge receiving chamber.
 12. Thedermal delivery device of claim 1, wherein said cartridge Comprisesopposed ends and said ends have convex surfaces and said burstablemembranes comprise polyolefin film having a thickness of between 0.3 and1.5 mils stretched taut over each of said convex surfaces at saidopposed ends of said end bonded to said convex surfaces, sealing saidpassage having a burst pressure of less than 5 atmospheres.
 13. Thedermal delivery device of claim 12, wherein said polyolefin film is apreferentially oriented polyolefin film and said oriented polyolefinfilm stretched over said opposed ends of said cartridge are oriented atdifferent angles.
 14. The dermal delivery device of claim 13, whereinsaid oriented polyolefin film is a uniaxially oriented polyethylenefilm, wherein said uniaxially oriented polyethylene film on one of saidopposed ends of said cartridge is oriented at approximately right anglesto the uniaxially oriented polyethylene film on the opposed end of saidcartridge.
 15. The dermal delivery device of claim 1, wherein saidhousing is formed of two opposed thermoformed polymeric sheets bondedtogether, and wherein said cartridge is encapsulated between said sheetsforming said chamber.
 16. The dermal delivery device of claim 15,wherein said medicament delivery device further comprises a manuallyactuated pressure actuator integrally formed from at least one of saidsheets.
 17. The dermal delivery device of claim 15, wherein saidmedicament delivery device further comprises a pressure actuator formedbetween said sheets communicating with said inlet and a generallycone-shaped diffuser formed between said sheets communicating with saidoutlet.
 18. The dermal delivery device as defined in claim 1, whereinsaid thin burstable membranes have a burst pressure of less than 5atmospheres.
 19. The dermal delivery device of claim 1 wherein thehousing is cylindrical and further comprises an opening for receivingthe cartridge.
 20. The dermal delivery device of claim 1, furthercomprising a piercing element capable of mechanically rupturing at leastone of said at bast one burstable membrane.
 21. A method for theintradermal delivery of a substance to a subject, said methodcomprising: positioning the device of claim 1 at a delivery site on theskin of a patient; intradermally administering the medicament bydispensing a diluent into the intradermal delivery device of claim 1through the inlet port with sufficient force to rupture the at least oneburstable membrane, thereby reconstituting the powdered medicament anddelivering the reconstituted medicament through the outlet port to themicrodevice to the intradermal region of the skin of the subject. 22.The method of claim 21, wherein the intradermal administration includespenetrating the stratum corneum of the skin with the microdevice priorto or concurrently with the delivery of the reconstituted medicament tothe skin of the subject.
 23. The method of claim 22, wherein therupturing of said at least one burstable membrane is accomplished by apiercing element contained within said device of claim
 1. 24. A dermaldelivery device, comprising: a housing having a chamber therein, aninlet port communicating with said chamber and an outlet portcommunicating with said chamber generally coaxially aligned with saidinlet port and with a microdevice comprising stratum corneum disruptingprotrusion selected from the group consisting of microabraders,microblades, and microneedles, a conduit leading to a microabradersurface and one or more microneedles; a cartridge located within saidchamber of said housing having opposed ends, a passage extending throughsaid cartridge through said opposed ends of said cartridge generallycoaxially aligned with said inlet and outlet ports of said housing, apowdered medicament in said passage, and burstable membranes coveringsaid passage, and bonded to said opposed ends of said cartridge, sealingsaid passage; and a container capable of controllably dispensing adiluent through the inlet port.
 25. A method for the dermal delivery ofa substance to a subject, said method comprising: positioning anintradermal delivery device at a delivery site to penetrate andsubstantially pierce the stratum corneum without substantiallypenetrating into the underlying dermis of the subject, said intradermaldelivery device comprising a housing comprising a chamber, at least oneinlet port communicating with said chamber, and at least one outlet portcommunicating with said chamber, said delivery device further comprisinga dry powdered medicament, a microdelivery device sized to penetrateinto the stratum corneum, intradermal space, or to disrupt the stratumcorneum, without substantially penetrating into the underlying dermis,at least one burstable membrane sealingly attached to one of said portsto retain said powdered medicament within said housing, and an adaptercommunicating with said at least one inlet port and adapted tocommunicate with a source of a fluid diluent; dispensing a diluentthrough the at least one inlet port with sufficient force to rupture theat least one burstable membrane and reconstitute the powdered medicamentwith the dispensed diluent and substantially simultaneously ejecting thereconstituted medicament through the at least one outlet port to themicrodevice at a delivery rate slower than the delivery rate of thediluent to the delivery device.
 26. A method for the epidermal deliveryof a substance to a subject, said method comprising: positioning thedevice of claim 1 at a delivery site on the skin of a patient;epidermally administering the medicament by dispensing a diluent intothe epidermal delivery device of claim 1 through the inlet port withsufficient force to rupture the at least one burstable membrane, therebyreconstituting the powdered medicament and delivering the reconstitutedmedicament through the outlet port to the microdevice to the epidermalregion of the skin of the subject.
 27. The method of claim 26, whereinthe epidermal administration includes moving said microdevice so thatsaid microdevice abrades an area of the skin, which abraded area has aplurality of grooves formed in the stratum corneum prior to orconcurrently with the delivery of the reconstituted medicament to theskin of the subject.
 28. The method of claim 27, wherein the epidermaladministration includes penetrating the stratum corneum of the skin withthe microdevice prior to or concurrently with the delivery of thereconstituted medicament to the skin of the subject.
 29. The method ofclaim 28, wherein the rupturing of said at least one burstable membraneis accomplished by a piercing element contained within said device ofclaim
 1. 30. A dermal delivery device comprising: a housing comprising achamber, an inlet port communicating with said chamber, and an outletport communicating with said chamber; a cartridge, wherein saidcartridge comprises a passage, a fluid receiving opening and a fluiddischarge opening, both openings communicating with said passage; a drypowdered medicament; a microdelivery device sized to penetrate into thestratum corneum, intradermal space, or to disrupt the stratum corneum,without substantially penetrating into the underlying dermis; at leastone burstable membrane sealingly attached to one of said ports to retainsaid powdered medicament within said chamber; and a fluid reservoircontaining a fluid diluent, communicating with said inlet port andadapted to deliver the fluid diluent to the chamber and to themicrodelivery device.
 31. The dermal delivery device of claim 30 whereinsaid powdered medicament is contained in said cartridge and said atleast one burstable membrane is sealingly attached to at least one ofsaid at least open cartridge opening.
 32. The dermal delivery device ofclaim 30, wherein said microdelivery device comprises one or morestratum corneum disrupting protrusions selected from the groupconsisting of microabraders, microblades, and microneedles.
 33. Thedermal delivery device of claim 30, wherein said microdelivery devicecomprises one or more microneedles, selected from the group consistingof solid microneedles, hollow microneedles and combinations thereof. 34.A method for the intradermal delivery of a substance to a subject, saidmethod comprising: positioning the device of claim 30 at a delivery siteon the skin of a patient; intradermally administering the medicament bydispensing a diluent from the reservoir of the intradermal deliverydevice of claim 30 through the inlet port with sufficient force torupture the at least one burstable membrane, thereby reconstituting thepowdered medicament and delivering the reconstituted medicament throughthe outlet port to the microdevice to the intradermal region of the skinof the subject.
 35. The method of claim 34, wherein the intradermaladministration includes penetrating the stratum corneum of the skin withthe microdevice prior to or concurrently with the delivery of thereconstituted medicament to the skin of the subject.
 36. The method ofclaim 35, wherein the rupturing of said at least one burstable membraneis accomplished by a piercing element contained within said device ofclaim 30.